Preparation of hydrazinoadamantane compounds

ABSTRACT

The preparation of hydrazinoadamantane compounds utilizing the starting materials of a haloadamantane compound with anhydrous hydrazine which are refluxed together at a temperature in the range of 25*-125* C. under a stream of nitrogen for a time in the range of 1-24 hours, the formed hydrazinoadamantane is treated with potassium hydroxide solution followed by extraction with ethyl ether and dried. Dry hydrogen chloride is passed into the ether solution and the resulting hydrochloride is filtered off and dried.

Uite States Thomas et a1.

[ March 6, 1973 PREPARATION OF HYDRAZINOADAMANTANE COMPOUNDS [75]Inventors: Telfer L. Thomas, Pittsford; Bola Vithal Shetty, Rochester,both of [73] Assignee: Pennwalt Corporation Philadelphia, Pa.

[22] Filed: Sept. 20, 1968 [21] Appl. No.: 761,280

[52] U.S. Cl.....260/563 P, 260/293.54, 260/294.8 B, 260/295 T, 260/296T, 260/327 R,

[51] Int. Cl ..C07c 109/02 [58] Field of Search..260/295 H, 296, 563,569, 514, 260/293 DA, 345.1

[56] References Cited OTHER PUBLICATIONS Evans, Rev. Pure Appl. Chem.12, 146-164 (1962), pp. 146-149 and 161 supplied.

Schleyer et al., J. Am. Chem. Soc. 83, 2,700-2,707 (1961). Westphal,Ber. 74, 759-776 and 1,365-1,372 (1941).

Primary Examiner-Henry R. Jiles Assistant Examiner-G. Thomas ToddAttorney- Charles E. Feeney [57] ABSTRACT 9 Claims, No DrawingsPREPARATION OF HYDRAZINOADAMANTANE COMPOUNDS The present inventionrelates to a method of preparation of hydrazinoadamantane compounds.

The l-hydrazinoadamantane compound and other compounds prepared by thismethod are useful as antiviral agents and as intermediate compounds inthe preparation of other pharmacological compounds.

An important object of the present invention is the provision of amethod of preparation of hydrazinoadamantanes which is substantiallysimpler in procedure than prior known methods. As exemplary of prior lowyield multi-step processes is that disclosed in the French Pat. No.1,491,581. The present process provides a one-step direct preparation of'the desired product.

Another object of the present invention is the provision of a processfor the preparation of hydrazinoadamantanes providing a high yield ofthe end product. The process provides excellent yields of up to 90-95percent.

A further object of the present invention is the provision of a processof preparation of hydrazinoadamantanes utilizing starting materials ofhaloadamantanes and anhydrous hydrazine where these materials arerefluxed under a stream of nitrogen to form the end product.

The present invention also comprehends the provision of a process ofpreparation of hydrazinoadamantane utilizing the starting materials ofhaloadamantane and silver p-toluenesulfonate in acetonitrile to form anintermediate of adarnantyl-p-toluenesulfonate, and this compound is thenrefluxed with anhydrous hydrazine under a stream of nitrogen to yieldthe hydrazinoadamantane.

Additional objects and advantages of our invention should be apparent tothose skilled in the art from the following description.

The novel process described herein comprises reacting anhydroushydrazine with a compound of the general formula:

halogen Where R, R, R H, alkyl, phenyl, phenylalkyl, aminoalkyl,adamantyl, hydrazinoadamantyl, pyridyl, -COOR", COR, NR R, OR

X CH NR, 0, S; n 1,2 R, R H, alkyl, phenyl,

phenylalkyl; where the alkyl group is preferably a lower alkyl, in otherwords, methyl, ethyl, propyl or the like.

As illustrative of typical derivatives of hydrazinoadamantane are thefollowing which are not meant to be limiting:

l,3-dimethyl-5-hydrazinoadamantane 1-hydrazino-3 -methoxyadamantane2-(3-hydrazinoadamant-lyl)-l-methylethylamine1-amino-3-hydrazinoadamantane 3-hydrazinol -adamantane carboxylic acidl-hydrazino-3 -phenyladamantane 3-hydrazino-l-adamantanol 1-ethyl-3-hydrazinoadam antane 1 -hydrazino-3-benzyladam antane 3 ,3 '-bishydrazino-l ,l '-biadamantane 3-hydrazinoadamant-l -yl methyl ketonel,3-dihydrazinoadamantane 4-( 3-hydrazinoadamant-l -yl )-pyridinel-dimethylaminc-3-hydrazinoadamantanel-isopropylamino-3-hydrazinoadamantane l-hydrazinohomoadamantane6-hydrazinohomoadamantane l-hydrazino-Z-azaadamantane5-hydrazino-2-azaadamantane 1-hydrazino-2-methyl-2-azaadamantane 1-hydrazino-2-oxaadam antane 5-hydrazino-2-oxaadamantanel-hydrazino-2-thiaadamantane 5-hydrazino-2-thiaadamantane The process offorming the hydrazinoadamantanes comprises reacting a haloadamantane, inother words, bromoadamantane or chloroadamantane with anhydroushydrazine preferably under a stream of nitrogen, carbon dioxide, argonor other inert gas in a temperature range of 25-125 C. for a timeinterval of 1-24 hours. The reaction is generally complete within 1-1'rhours but no harm is done by refluxing for a longer period of time. Thereaction can be carried out at higher temperatures under pressure butthis is not necessary and does not improve the reaction or the yield.The reaction proceeds very slowly, however, at room temperature andbelow.

The anhydrous hydrazine is used in excess in the reaction mixturebecause it is a good solvent for the end product. Also, by using anexcess of hydrazine, no disubstituted product is obtained, and theadamantane is unstable in a neutral solution but stable in hydrazine.

After the reaction has been completed, the hot solution is added to anaqueous solution of an alkali metal salt such as potassium, sodium orammonium hydroxide, sodium chloride; preferably to a cold 45 percentpotassium hydroxide solution, which dissolves the excess hydrazine. Thehydrazinoadamantane product is extracted with ether, and the ethersolution is washed with additional alkali metal hydroxide solution anddried, for example over magnesium sulfate. The purifledhydrazinoadamantane in ether solution is then treated with an anhydroushydrogen chloride to obtain a hydrazinoadamantane hydrochloride, whichis filtered off, washed with ether and and dried, for example in vacuoover phosphorus 'pentoxide and sodium hydroxide. The end product isunchanged by recrystallization from isopropanol. The hydrochloride ofthe hydrazinoadamantane is stable whereas the hydrazinoadamantane is notstable in the air.

The following examples illustrate the above procedure for forming thel-hydrazinoadamantane.

EXAMPLE 1 Into a 50 ml. nitrogen flushed flask fitted with a nitrogeninlet tube and a condenser was placed 5.3 gm. l-bromoadamantane and 30ml. anhydrous hydrazine. The mixture was stirred magnetically andrefluxed under a slow stream of nitrogen for 3 hours (refluxingoccurring at approximately 115 C.).

The hot solution was then poured into 125 ml. of cold 45 percentpotassium hydroxide solution and extracted with three 100 ml. portionsof ethyl ether. The ether solution was then washed with three 100 ml.portions of 45 percent potassium hydroxide solution and dried overmagnesium sulfate. Dry hydrogen chloride was passed into the ethersolution and the resulting hydrochloride was filtered off, washed withether and dried in vacuo over phosphorus pentoxide and sodium hydroxide.Obtained was 4.6 gm. of analytically pure product melting at 250253 C.;the product being a 93 percent yield.

EXAMPLE 2 Into a flask prepared as in Example 1 was placed 5.3 gm.l-isopropylamino-3-bromoadamantane and 30 ml. anhydrous hydrazine. Themixture was stirred and refluxed under a stream of nitrogen for 4 hours.The hot solution was added to 125 ml. of cold 45 percent potassiumhydroxide solution and the product extracted with three 100 ml. portionsof ethyl ether. The ether solution was washed with 100 ml. portions of45 percent potassium hydroxide solution, dried over magnesium sulfate,and dry hydrogen chloride passed into the ether solution to form thehydrochloride. This product is filtered off, washed with ether and driedin vacuo over phosphorus pentoxide and sodium hydroxide. Yield ofl-isopropylamino-3-hydrazinoadamantane was 90 percent.

In these reactions, the bromoadamantane or other haloadamantane issubstituted with the radicals desired in the end product. The hydrazineradical always replaces the halogen radical on the adamantane ring, andthe positioning of the hydrazine radical depends on the initialplacement of the halogen radical on the ring. From the previouslymentioned derivatives, the bromine, chlorine or other halogen can bepositioned at the 1, 3 or 5 position on the adamantane, and theutilization of an adamantane having two halogen radicals will provide adisubstituted hydrazinoadamantane. Following the general procedure ofExamples 1 and 2 using substituted haloadamantanes, the derivatives ofl-hydrazinoadamantane previously listed will be formed.

The present invention also comprehends an additional two-step method ofpreparing hydrazinoadamantanes where a tosylate is initially formed andthen treated with hydrazine to form the hydrazinoadamantane. In thismethod, bromoadamantane or other haloadamantane is treated with silverp-toluenesulfonate in acetonitrile and gives a virtually quantitativeyield of adamantyl tosylate. When then refluxed with anhydroushydrazine, a 60 percent yield of hydrazinoadamantane is obtained. Thefollowing example illustrates this method.

EXAMPLE 3 Adamantyl p-toluenesulfonate was prepared crude in 98 percentyield as follows: 11.4 gm. of l-bromoada- 5 mantane was added to a 0 C.solution of 14.8 gm. silver p-toluenesulfonate in 150 ml. acetonitrileunder protection from light. The reaction mixture was allowed to warm toroom temperature (25 C.) over two hours and the precipitated silverbromide was filtered off. The adamantyl p-toluenesulfonate wasconcentrated to dryness on a rotary evaporator yielding 9.5 gm. productmelting at 69-77 C. Exclusion of water was necessary during the reactionand work up to prevent partial hydrolysis to l-adamantol.

Conversion of the tosylate to l-hydrazinoadamantane was accomplished byrefluxing the l-adamantyl ptoluenesulfonate (5 gm.) in ml. of anhydroushydrazine under a nitrogen stream for 18 hours. The hot solution waspoured into 125 ml. of 45 percent potassium hydroxide and the productwas extracted with three 100 ml. portions of ether. The ether solutionwas extracted with three 100 ml. portions of 45 percent potassiumhydroxide and dried over magnesium sulfate. The l-hydrazinoadamantanesolution was treated with anhydrous hydrogen chloride yielding 1.9 gm.of l-hydrazinoadamantane hydrochloride with a melting point of 252-254C.; unchanged by recrystallization from isoproponal ml/gm Having thusdisclosed our invention, we claim:

1. A process for preparing a hydrazinoadamantane which comprises heatinga solution made up of: (a) a compound of the following structure:

where R, R R are hydrogen and lower alkyl and X is halogen andp-toulene-sulfonate and (b) excess anhydrous hydrazine.

2. A process as in claim 1 wherein the compound is l-bromoadamantane.

3. A process as in claim 1 wherein the compound is adamantylp-toluensulfonate.

4. A process for the preparation of a hydrazinoadamantane whichcomprises heating a solution made up of: (a) a compound of the followingstructure:

ture is refluxed for l to 3 hours under an inert atmosphere.

dried.

9. A process as set forth in claim 8, in which anhydrous hydrogenchloride is added to the dried ether solution to form the stablehydrochloride which is filer 5 tered off, washed in ether, and dried invacuo.

1. A process for preparing a hydrazinoadamantane which comprises heating a solution made up of: (a) a compound of the following structure: where R, R1, R2, are hydrogen and lower alkyl and X is halogen and p-toulene-sulfonate and (b) excess anhydrous hydrazine.
 2. A process as in claim 1 wherein the compound is 1-bromoadamantane.
 3. A process as in claim 1 wherein the compound is adamantyl p-toluensulfonate.
 4. A process for the preparation of a hydrazinoadamantane which comprises heating a solution made up of: (a) a compound of the following structure: where R, R1, R2 are hydrogen and lower alkyl; and (b) excess anhydrous hydrazine.
 5. A process as set forth in claim 1, in which said mixture is reacted in a temperature range of 25*-125* C. over a time range of 1 to 24 hours.
 6. A process as set forth in claim 1, in which said mixture is refluxed for 1 to 3 hours under an inert atmosphere.
 7. A process as set forth in claim 1, in which said reacted solution is poured into an alkali metal salt solution to dissolve the excess hydrazine and the remaining product is extracted with ether.
 8. A process as set forth in claim 7, in which the ether solution is washed with alkali metal salt solution and dried. 